MEDNIK syndrome is a rare autosomal recessive disease characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma, and caused by variants in the adaptor-related protein complex 1 subunit sigma 1 (AP1S1) gene. This gene encodes the σ1A protein, which is a subunit of the adaptor protein complex 1 (AP-1), a key component of the intracellular protein trafficking machinery. Previous work identified three AP1S1 nonsense, frameshift and splice-site variants in MEDNIK patients predicted to encode truncated σ1A proteins, with consequent AP-1 dysfunction. However, two AP1S1 missense variants (c.269 T > C and c.346G > A) were recently reported in patients who presented with severe enteropathy but no additional symptoms of MEDNIK. This condition was described as a novel non-syndromic form of congenital diarrhea caused specifically by the AP1S1 missense variants. In this study, we report two patients with the same c.269 T > C variant, who, contrary to the previous cases, presented as complete MEDNIK syndrome. These data substantially revise the presentation of disorders associated with AP1S1 gene variants and indicate that all the identified pathogenic AP1S1 variants result in MEDNIK syndrome. We also provide a series of functional analyses that elucidate the impact of the c.269 T > C variant on σ1A function, contributing to a better understanding of the molecular pathogenesis of MEDNIK syndrome. KEY MESSAGES: A missense AP1S1 c.269 T > C (σ1A L90P) variant causes full MEDNIK syndrome. The σ1A L90P variant is largely unable to assemble into the AP-1 complex. The σ1A L90P variant fails to bind [DE]XXXL[LI] sorting motifs. The σ1A L90P variant results in loss-of-function of the protein.

CLIP Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatrics 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Section on Intracellular Protein Trafficking Neurosciences and Cellular and Structural Biology Division Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD USA

Zobrazit více v PubMed

García-Cazorla A, Oyarzábal A, Saudubray JM et al (2022) Genetic disorders of cellular trafficking. Trends Genet 38:724–751. 10.1016/J.TIG.2022.02.012 PubMed

Dell’Angelica EC, Bonifacino JS (2019) Coatopathies: Genetic Disorders of Protein Coats. Annu Rev Cell Dev Biol 35:131–168. 10.1146/ANNUREV-CELLBIO-100818-125234 PubMed PMC

Sanger A, Hirst J, Davies AK, Robinson MS (2019) Adaptor protein complexes and disease at a glance. J Cell Sci 132(20):jcs222992. 10.1242/JCS.222992 PubMed

Janvier K, Kato Y, Boehm M et al (2003) Recognition of dileucine-based sorting signals from HIV-1 Nef and LIMP-II by the AP-1 gamma-sigma1 and AP-3 delta-sigma3 hemicomplexes. J Cell Biol 163:1281–1290. 10.1083/JCB.200307157 PubMed PMC

Doray B, Lee I, Knisely J et al (2007) The gamma/sigma1 and alpha/sigma2 hemicomplexes of clathrin adaptors AP-1 and AP-2 harbor the dileucine recognition site. Mol Biol Cell 18:1887–1896. 10.1091/MBC.E07-01-0012 PubMed PMC

Mattera R, Boehm M, Chaudhuri R et al (2011) Conservation and diversification of dileucine signal recognition by adaptor protein (AP) complex variants. J Biol Chem 286:2022–2030. 10.1074/JBC.M110.197178 PubMed PMC

Ohno H, Stewart J, Fournier MC et al (1995) Interaction of tyrosine-based sorting signals with clathrin-associated proteins. Science 269:1872–1875. 10.1126/SCIENCE.7569928 PubMed

Montpetit A, Côté S, Brustein E et al (2008) Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord. PLoS Genet 4(12):e1000296. 10.1371/JOURNAL.PGEN.1000296 PubMed PMC

Saba TG, Montpetit A, Verner A et al (2005) An atypical form of erythrokeratodermia variabilis maps to chromosome 7q22. Hum Genet 116:167–171. 10.1007/S00439-004-1193-8 PubMed

Martinelli D, Travaglini L, Drouin CA et al (2013) MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy. Brain 136:872–881. 10.1093/BRAIN/AWT012 PubMed

Incecik F, Bisgin A, Yılmaz M (2018) MEDNIK syndrome with a frame shift causing mutation in AP1S1 gene and literature review of the clinical features. Metab Brain Dis 33:2065–2068. 10.1007/S11011-018-0313-4 PubMed

Lu JG, Namjoshi SS, Niehaus AD et al (2023) Clinicopathologic Features of IDEDNIK (MEDNIK) Syndrome in a Term Infant: Histopathologic Features of the Gastrointestinal Tract and Report of a Novel AP1S1 Variant. Pediatr Dev Pathol 26:406–410. 10.1177/10935266231177402 PubMed

Klee KMC, Janecke AR, Civan HA et al (2020) AP1S1 missense mutations cause a congenital enteropathy via an epithelial barrier defect. Hum Genet 139:1247–1259. 10.1007/S00439-020-02168-W PubMed PMC

Mattera R, Williamson CD, Ren X, Bonifacino JS (2020) The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear distribution of AP-4 and its cargo ATG9A. Mol Biol Cell 31:963–979. 10.1091/MBC.E19-11-0658 PubMed PMC

Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760. 10.1093/BIOINFORMATICS/BTP324 PubMed PMC

Koboldt DC, Zhang Q, Larson DE et al (2012) VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res 22:568–576. 10.1101/GR.129684.111 PubMed PMC

Li H, Handsaker B, Wysoker A et al (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics 25:2078–2079. 10.1093/BIOINFORMATICS/BTP352 PubMed PMC

Kircher M, Witten DM, Jain P et al (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310–315. 10.1038/NG.2892 PubMed PMC

Quinodoz M, Peter VG, Bedoni N et al (2021) AutoMap is a high performance homozygosity mapping tool using next-generation sequencing data. Nat Commun 12:518. 10.1038/S41467-020-20584-4 PubMed PMC

Jain S, Farías GG, Bonifacino JS (2015) Polarized sorting of the copper transporter ATP7B in neurons mediated by recognition of a dileucine signal by AP-1. Mol Biol Cell 26:218–228. 10.1091/MBC.E14-07-1177 PubMed PMC

Ren X, Farías GG, Canagarajah BJ et al (2013) Structural basis for recruitment and activation of the AP-1 clathrin adaptor complex by Arf1. Cell 152:755–767. 10.1016/J.CELL.2012.12.042 PubMed PMC

Theos AC, Tenza D, Martina JA et al (2005) Functions of adaptor protein (AP)-3 and AP-1 in tyrosinase sorting from endosomes to melanosomes. Mol Biol Cell 16:5356–5372. 10.1091/MBC.E05-07-0626 PubMed PMC

Usmani MA, Ahmed ZM, Magini P et al (2021) De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy. Am J Hum Genet 108:1330–1341. 10.1016/J.AJHG.2021.05.007 PubMed PMC

Boyden LM, Atzmony L, Hamilton C et al (2019) Recessive Mutations in AP1B1 Cause Ichthyosis, Deafness, and Photophobia. Am J Hum Genet 105:1023–1029. 10.1016/J.AJHG.2019.09.021 PubMed PMC

Alsaif HS, Al-Owain M, Barrios-Llerena ME et al (2019) Homozygous Loss-of-Function Mutations in AP1B1, Encoding Beta-1 Subunit of Adaptor-Related Protein Complex 1, Cause MEDNIK-like Syndrome. Am J Hum Genet 105:1016–1022. 10.1016/J.AJHG.2019.09.020 PubMed PMC

Meriç R, Ercan-Sencicek AG, Alkaya DU et al (2021) A patient with mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, keratodermia syndrome caused by AP1B1 gene variant. Clin Dysmorphol 30:54–57. 10.1097/MCD.0000000000000350 PubMed

Faghihi F, Khamirani HJ, Zoghi S et al (2022) Phenotypic spectrum of autosomal recessive Keratitis-Ichthyosis-Deafness Syndrome (KIDAR) due to mutations in AP1B1. Eur J Med Genet 65:104449. 10.1016/J.EJMG.2022.104449 PubMed

Ito Y, Takeichi T, Igari S et al (2021) MEDNIK-like syndrome due to compound heterozygous mutations in AP1B1. J Eur Acad Dermatol Venereol 35:e345–e347. 10.1111/JDV.17098 PubMed

Vornweg J, Gläser S, Ahmad-Anwar M et al (2021) Identification of compound heterozygous mutations in AP1B1 leading to the newly described recessive keratitis-ichthyosis-deafness (KIDAR) syndrome. Br J Dermatol 184:1190–1192. 10.1111/BJD.19815 PubMed

Zhong J, Cui Y, Guo J et al (2014) Resolving chromosome-centric human proteome with translating mRNA analysis: a strategic demonstration. J Proteome Res 13:50–59. 10.1021/PR4007409 PubMed

Rodríguez-Castañeda F, Lemma RB, Cuervo I et al (2018) The SUMO protease SENP1 and the chromatin remodeler CHD3 interact and jointly affect chromatin accessibility and gene expression. J Biol Chem 293:15439–15454. 10.1074/JBC.RA118.002844 PubMed PMC